The disease differs from most other forms of acquired botulism in that active colonization by toxin producing bacteria cause disease, rather than exposure to pre-formed toxin. Although this form generally only occurs in young infants, rarely the disease may present in older children and adults (as adult intestinal botulism). This chapter will not specifically discuss the managements of other forms of botulism.

Clinical features

The clinical features of botulism are similar regardless of how the disease is acquired (e.g. intestinal colonization, direct ingestion/inhalation of spores or wound infection). Infant botulism presents along a wide spectrum, from mild disease which may be transient to severe life threatening respiratory insufficiency at presentation or with progression. Typically the disease presents with a descending symmetric paralysis, usually involving the muscles of the cranial nerves first, followed by those of the trunk, extremities and diaphragm.

Manifestations of disease in affected infants can present first to the parents as poor feeding, constipation or flat facial expressions. The initial cranial nerve manifestations can present with oculomotor and pupillary palsies, difficulty with gagging and sucking (manifested by gurgling or drooling), and ptosis. As disease progresses autonomic signs may become apparent, such as reduced tearing and salivation, as well as fluctuations in heart rate, blood pressure and skin perfusion.

In some atypical cases (more common in affected infants less than 2 months of age) a rapid deterioration and presentation with respiratory collapse can occur within hours of initial signs of illness or at the onset of noticeable symptoms. The typical complaints of constipation and cranial nerve palsies may be initially absent in these cases. Botulism has been implicated as a cause in some series of patients with sudden infant death syndrome (SIDS).

Physical exam findings may give clues to the diagnosis, in particular a hypotonic infant with poor head control but seemingly alert appearing. Vital signs should be monitored and may show fluctuations of pulse and blood pressure. Fever is typically absent. Cranial nerve findings are not universally abnormal at presentation, but with progression all may be affected, in particular those related to gagging and swallowing.

A dry mouth and pharynx may be present due to parasympathetic cholinergic blockade, giving the appearance of dehydration. Deep tendon reflexes may be diminished or absent, along with poor anal sphincter tone. Sensation is typically intact. The skin may appear to be flushed.

Key management points

Most infants will require significant supportive care, with one study showing that 50% will require mechanical ventilation, and most will require intensive care management. A high index of suspicion is critical to appropriately diagnose and manage infants with botulism, as the diagnosis often goes unsuspected, and early initiation of specific therapy (Botulism immune globulin intravenous [BIG-IV or babyBIG]) has been proven to improve clinical outcomes and reduce overall care costs.

All infants with compatible clinical history, signs or symptoms of botulism should be hospitalized for monitoring and further management.

Botulism immune globulin intravenous (BIG-IV) should be administered as early as possible in the course, even when the diagnosis is only suspected and not proven. Therapy should not be delayed pending formal confirmation of the diagnosis. Access to BIG-IV can be obtained from the California Department of Health Services, Infant Botulism Treatment and Prevention Program at (510)231-7600, or online at www.infantbotulism.org.

Further management is supportive:

Appropriate respiratory support is vital to prevent sudden ventilatory collapse and subsequent hypoxia.

The syndrome of inappropriate anti-diuretic hormone (SIADH) has been reported as an occasional complication of infant botulism requiring appropriate monitoring.

Nutritional support should be provided with enteral therapy being the preferred route. Continuous enteral feeds are generally well tolerated and may be used in preference to intravenous hyperalimentation.

Observation for and management of complications such as aspiration pneumonia, urinary tract infection, acute otitis media and other complications of long term hospitalization.

2. Emergency Management

Recognition of impending respiratory failure is the most important initial management component for emergency support. Approximately half of all affected infants will require mechanical ventilation at some point during their course of disease.

Vital signs should be monitored for signs of autonomic instability leading to fluctuations of blood pressure and heart rate.

Dehydration may be present initially secondary to poor feeding. This should be evaluated clinically and treated as appropriate.

Electrolytes should be evaluated for disturbances secondary to dehydration and poor feeding, along with the potential complication of SIADH leading to hyponatremia.

Infants under 2 months of age presenting with botulism are at higher risk of sudden, unexpected collapse and may require pre-emptive intubation.

All infants with suspected botulism should be admitted to the hospital and monitored initially in an ICU level setting.

Botulism is a nationally reportable disease, and any suspected case should be immediately reported to local and state health departments.

3. Diagnosis

Diagnostic criteria and tests

The diagnosis of infant botulism requires a high index of suspicion, as routine laboratory testing is generally normal and unhelpful. The confirmatory testing for infant botulism relies on detection of Clostridium botulinum in stool samples, either through culture and isolation of the organism and spores or by detection of toxin. As many infants presenting with botulism will have a history of constipation, obtaining a stool specimen can be difficult but can be aided by use of a mild enema using sterile non-bacteriostatic water (rather than saline) for diagnostic purposes.

Contact with the local state health department immediately upon recognition of a potential case of botulism is critical, as specific diagnostic testing is only performed by certain reference laboratories within the United States at selected public health laboratories and the CDC. If contact with the local state health department cannot be made, the CDC Emergency Operations Center (770-488-7100) should be contacted to provide consultation.

Identification of toxin through a mouse neutralization assay is the most reliable confirmatory test for suspected cases of infant botulism, and may take several days to provide a result. Stool culture for C. botulinum generally takes 5-10 days. Stool specimens should be refrigerated prior to shipment to a reference laboratory for testing. Toxin and culture assays can be positive in stool for up to 5 months after the onset of infant botulism.

For other potential forms of botulism, including foodborne and wound, samples can also be obtained from potential contaminated food sources, wounds and serum for toxin assays. These are generally unhelpful in the diagnosis of infant botulism, and serum assays for toxin in particular have low yield in making the diagnosis.

Electromyogram (EMG) findings may be supportive of botulism but are not confirmatory. Early in the course of disease specific EMG findings may not be present. Specific findings include: short duration small-amplitude motor potentials, and an abnormal incremental response to repetitive nerve stimulation at rates of 20-50 Hz, coupled with normal conduction velocity and sensory nerve function.

Tensilon testing with edrophonium chloride to rule out myasthenia gravis is generally not recommended for cases of infant botulism that are strongly suspected, as false positive results have been reported in some adults with botulism.

Therapy should not be delayed for complete confirmation of stool studies as this may take several days. A compatible clinical history coupled with suggestive EMG findings should be used to initiate early management steps for infant botulism and contact with the California Department of Health Services, Infant Botulism Treatment and Prevention Program at (510)231-7600.

How do I know this is what the patient has?

Nonspecific testing for botulism is rarely helpful other than to rule out other diagnostic possibilities. Routine analysis of complete blood counts, serum chemistries, inflammatory markers and cerebrospinal fluid are typically normal. Occasional complications such as dehydration and SIADH can occur and cause electrolyte disturbances, but these are non-specific.

A presumptive diagnosis of infant botulism can be made based upon typical historical and physical exam findings in many cases. Although EMG may be supportive of the diagnosis, it is often unnecessary in infant cases if the clinical features are sufficiently suggestive. Ultimate confirmation can be obtained through a specific
C. botulinum toxin assay or culture of stool specimens for infant botulism.

What else could it be?

The most common alternative diagnoses considered in the differential diagnosis of infant botulism as reported by a review on use of botulism immune globulin in patients initially suspected of having infant botulism include:

metabolic disorders

glutaric aciduria type I

maple syrup urine disease

Leigh's syndrome

succinic semialdehyde dehydrogenase deficiency

mitochondiral disorders

spinal muscular atrophy type I

infectious diseases

enteroviral encephalitis

RSV bronchiolitis

Probable viremia

Guillain-Barré syndrome with Miller-Fisher variant

Lambert-Eaton syndrome secondary to neuroblastoma

Cerebral atrophy secondary to in utero drug exposure

Cerebral infarctions

Spinal epidural hematoma

Diaphragmatic paralysis

Central demyelinating disease

Other disorders which must be considered include myasthenia gravis, tick paralysis, drug or toxin ingestions and sepsis.

Clinical and laboratory features may often be helpful in distinguishing these other conditions from botulism. Metabolic disorders frequently present with vomiting, acidosis, or neurodevelopmental declines that are not typical features of botulism. Spinal muscular atrophy type I tends to spare cranial nerves, is slowly progressive and may be suspected in some cases on the basis of family history.

Infectious diseases frequently will present with fever - generally absent in botulism - and specific findings related to the source of the infection. Guillain-Barré disease generally presents with ascending paralysis, may have associated sensory defects and often will have an associated elevated CSF protein. Myasthenia gravis typically does not present in the infant age group outside of the neonatal period and tends to have much more dramatic waxing and waning features, with ptosis alone being a prominent feature rather than generalized weakness. A careful exam looking for ticks can be helpful in cases of tick paralysis.

Confirmatory tests

Specific confirmation of the diagnosis of infant botulism relies on detection of C. botulinum toxin in stool, or culture of C. botulinum from stool specimens. Contact with the local state health department immediately upon recognition of a potential case of botulism is critical, as specific diagnostic testing is only performed by certain reference laboratories within the United States.

Contact the California Department of Health Services, Infant Botulism Treatment and Prevention Program at (510)231-7600, or online at www.infantbotulism.org, early in the course to provide assistance with laboratory diagnosis and receipt of botulism immune globulin intravenous (BIG-IV) is recommended. Botulism is a nationally reportable disease and any suspected case should be immediately reported to the local and state health departments.

4. Specific Treatment

All infants with suspected infant botulism on the basis of clinical grounds should be hospitalized. Specific therapy with botulism immune globulin intravenous (BIG-IV or BabyBig) should be given as early as possible in the course of the disease, as delay in therapy has been associated with prolonged recovery and need for longer period of mechanical ventilation. Administration of therapy should not be delayed pending specific confirmation of the diagnosis by toxin or culture assays.

BIG-IV is available only from one source in the United States, the California Department of Health Services (CDHS), Infant Botulism Treatment and Prevention Program at (510) 231-7600, or online at www.infantbotulism.org, which can provide the product to any state. The CDHS should be contacted as soon as the diagnosis is strongly suspected to arrange for transport of the drug early in the course of illness.

BIG-IV is highly effective for the treatment of infant botulism. It has been shown in a randomized controlled trial of 122 patients with infant botulism to reduce mean duration of hospitalization (2.6 vs 5.7 weeks), intensive care (reduction of 3.2 weeks), mechanical ventilation (reduction of 2.6 weeks) and supplemental nutrition (reduction of 6.4 weeks). In addition, BIG-IV was shown to be cost effective, as mean hospital charges were reduced by $88,600 (in 2004 U.S. dollars).

The same study also involved an open label review of 366 infants with confirmed botulism, demonstrating the need for timely initiation of BIG-IV with a difference of 2.0 weeks total hospitalization for those treated within 3 days of initial hospital admission versus 2.9 weeks for those treated between 4-7 days after hospitalization. Neutralizing antibodies persist for at least 6 months after the administration of BIG-IV, which is sufficient time to allow for clearance of the organism from intestinal colonization.

Equine botulism antitoxin, used for adult onset forms of botulism, is not used in the management of infant botulism. Antibiotics are not recommended as specific therapy for infant botulism and have not been shown to provide benefit. Their use should be discouraged unless a secondary bacterial infection is suspected.

Drugs and dosages

Botulism Immune Globulin Intravenous (BIG-IV or BabyBIG):

Dosage 100 mg/kg given as a single intravenous infusion.

Administer BabyBIG intravenously at 0.5 mL per kg body weight per hour (25 mg/kg/h). If no untoward reactions occur after 15 minutes, the rate may be increased to 1.0 mL/kg/h (50 mg/kg/h). DO NOT EXCEED THIS RATE OF ADMINISTRATION.

Only available through California Department of Health Services (CDHS), Infant Botulism Treatment and Prevention Program at (510)231-7600, or online at www.infantbotulism.org.

5. Disease monitoring, follow-up and disposition

Infant botulism has a high mortality without adequate management, with respiratory failure being the primary cause of death in those affected. Approximately 50% of infants will require mechanical ventilation, with prompt intubation being a key intervention to decrease morbidity and mortality. Key respiratory indicators that should be monitored include pulse oximetry, blood gas analysis, and ventilatory status, along with clinical abilities related to coughing, gagging, sucking and swallowing.

Infants under 2 months of age may have a rapid deterioration leading to a catastrophic collapse that is not fully predictable based on their apparent disease progression and should be followed extremely closely, with strong consideration for pre-emptive intubation. In older infants the tempo of progression over the first 24 hours often portends how rapidly the disease will continue to progress. Infants will generally continue to have progression of disease over the first 1-2 weeks followed by a plateau for several weeks and then slow recovery over weeks to months.

Other important monitoring parameters include perfusion status, fluid and electrolyte balance, and nutrition. SIADH has been associated with infant botulism and should be monitored appropriately. Secondary infections are a concern in those with infant botulism, and include mainly hospital acquired infections such as aspiration pneumonia, urinary tract infections and occasionally otitis media.

With prompt initiation of BIG-IV, the total duration of need for intubation, hospitalization and nutritional support is dramatically decreased. Prior to the routine use of BIG-IV, the total duration of hospitalization was 1-2 months for infants with botulism, with an average of approximately 3 weeks of mechanical ventilation. With early specific therapy, the need for intubation is reduced to about 2 weeks with an average length of hospitalization of approximately 3 weeks.

All infants with suspected botulism should be admitted to the hospital in an intensive care setting for monitoring. The infant should not be transferred out of the ICU setting until the course and severity of the illness have been determined and a probable need for mechanical ventilation has been ruled out, which may take several days.

Isolation: Standard precautions are indicated for infants with suspected or proven botulism. Human cases are not considered to be contagious and no cases of person to person spread have been identified.

Misdiagnosis

In most cases the clinical and physical findings of botulism in infancy are quite specific, making overdiagnosis unlikely when coupled with specific diagnostic testing. However, certain clues may occur which could point to an alternative diagnosis. Continued decline in neurologic function despite the administration of BIG-IV may be an indicator of another neuromuscular disease, such as spinal muscular atrophy or Guillain-Barré syndrome.

The manifestations of impaired sensorium, developmental delay, and/or vomiting or acidosis should prompt consideration of a metabolic syndrome. Fever is usually not a feature of infant botulism, and if present should prompt consideration of other causes, such as CNS infections, sepsis, etc.

Follow up

At discharge, infants will need close follow up with their primary pediatrician and other subspecialists from whom they may need ongoing care. Full recovery may take months, requiring ongoing outpatient management from neurology and pulmonology if necessary. Referrals to speech therapy, physical therapy and occupational therapy may be necessary to optimize recovery, activity and nutrition.

Pathophysiology

Infant botulism differs from adult forms of the disease in that active colonization of the gastrointestinal tract by viable organisms leads to disease, rather than ingestion or exposure to pre-formed toxins. Inadvertent ingestion of botulism spores leads to intestinal colonization in these infants, followed by production of toxin within the gastrointestinal tract, which is then absorbed into the systemic circulation.

Botulinum toxin inhibits acetylcholine release at the neuromuscular junction, leading to profound weakness of skeletal muscle and to a lesser extent smooth muscle. Although multiple strain types exist, most cases within the United States are due to toxins type A and B, with disease manifestations generally being most severe for type A. Competitive bowel flora appears to be inhibitory to the growth of C. botulinum within the gut, which likely accounts for the increased susceptibility of infants (especially very young infants) to this form of disease, and explains why older children and adults are generally resistant to intestinal botulism.

Epidemiology

Infant botulism is a rare disease caused by Clostridium botulinum, a naturally occurring environmental agent that is a Gram positive, anaerobic, heat resistant, spore forming bacillus. Disease in infants is caused by the ingestion of spores which then germinate and produce neurotoxin. The two major toxin types (A and B) each account for roughly half of all human cases, with toxin A being more prevalent in the western United States, and type B having a more diffuse east/west distribution but only occurring from middle-northern U.S. latitudes.

The source of acquisition of the organism is generally unknown and is most often felt to be related to ingestion of contaminated environmental dust or soil. Construction and other events causing soil disruption may be more likely to release environmental soil reservoirs of C. botulinum, and are often historically associated with onset of disease by parents.

Although ingestion of honey is often cited as a potential source of exposure to C. botulinum, it represents a very uncommon proven cause for infection in U.S. infants. Light and dark corn syrups also are often considered a potential source, but no case of infant botulism has been proven to be attributed to these. Most cases occur in infants who have been exclusively breastfed at the time of introduction of non-human milk products. In 2007 there were 91 laboratory confirmed cases of infant botulism in the United States, with a median age of 15 weeks.

Prognosis

In general, with prompt diagnosis and appropriate management, the outcome of infant botulism is excellent. As reported in the controlled trial establishing the utility of BIG-IV, the mortality rate for infant botulism in the United States is less than 1%. Recovery is generally complete, but it may take weeks or months to regain normal motor function and activity. Brain functioning is not affected as the toxin does not cross the blood brain barrier, so an affected infant will retain normal alertness and cognitive functioning during the illness.

Return of motor function requires regrowth of nerve endings at the motor end plate. Many long term complications of botulism are secondary to consequences of prolonged hospitalization and mechanical ventilation causing nosocomial infections, rather than directly related to the organism itself. There have been no reports of proven reinfection with recurrent illness related to infant botulism.